Assessment of tumorigenicity and efficacy of transplantation therapy with ESC-derived neural cells by PET imaging

Objectives Recent advancement in embryonic stem cell (ESC) has led to the expectation of regenerative therapy with transplantation for Parkinson's disease (PD) which replaces the lost dopaminergic neurons. However, little is known about suitable differentiation state which produces large therapeutic effects for PD in keeping with safety. Here we measured the growth and function of ESC-derived cells in different stages of neural differentiation implanted in the brains of primate models of PD using PET.

Methods Four kinds of differentiated cells from human ESC were obtained by the modified stromal cell-derived inducing activity method. ESC-derived neuronal cells were implanted unilaterally in the putamen of primate models of PD. We performed PET scan with [¹⁸F]FLT and [¹⁸F]DOPA for evaluation of tumorigenicity and DA synthetic capacity, respectively. The [¹⁸F]DOPA uptake rate (K_i) was calculated using the Patlak graphical analysis method.

Results [¹⁸F]FLT-PET showed a high focal uptake in the implanted region only in the monkey that received d14-spheres. In contrast, [¹⁸F]FLT uptake in the region received d28-spheres showed little change, compared to the control region treated with injections of culture medium. [¹⁸F]DOPA-PET revealed increase in uptake of [¹⁸F]DOPA in the region received d35- and d42-spheres, in which K_i value of the d42-sphere was higher than that of d35-spheare. In addition, increases in K_i value were significantly correlated with changes in the neurological scores in each monkey, suggesting that dopamine production by the grafted cells largely contributed to their behavioral improvements.

Conclusions PET imaging with [¹⁸F]FLT and [¹⁸F]DOPA provided the results that transplantation of neural cells derived from human ESC can restore DA function without tumorigenicity in the primate model of PD by controlling the differentiation of graft cells. PET molecular imaging is undeniably capable for assessment of efficacy and safely of transplantation therapy with stem cells.